Kinetics of response to iloprost evaluated by laser speckle contrast analysis in systemic sclerosis.

OBJECTIVE: Iloprost (ILO) is recommended for the treatment of systemic sclerosis (SSc) microangiopathy, but there is no common consensus on its optimal dosage. The aim of this study is to evaluate the kinetics of response to ILO administered in a daily outpatient scheme in SSc subjects using laser speckle contrast analysis (LASCA). METHOD: Adult SSc patients in stable therapy with ILO administered for 6 h for 2 consecutive days every 4 weeks were enrolled. Peripheral finger perfusion was assessed by LASCA. Each patient underwent five LASCA evaluations: before and after each day of ILO (D1pre, D1post, D2pre, and D2post) and after 4 weeks (D30). RESULTS: Twenty-seven SSc patients (77.8% female, mean age 61.5 years) were enrolled. LASCA showed an increase in perfusion at the end of each ILO course, but on the second day (both D1pre vs D2pre and D2pre vs D2post) the increase was no longer significant in half of the fingers. Moreover, compared to D1post, at the beginning of the second ILO day most of the fingers had already shown a significant reduction in perfusion. After 1 month, there were no statistically significant differences between the perfusion values of D1pre and D30. CONCLUSION: This LASCA study highlights the transience of the vasoactive effect of ILO, with a perfusion benefit that is completely lost after 1 month. The brevity of the perfusion effect of ILO and the use of LASCA are elements to consider in the design of future SSc trials to determine the optimal ILO dosage.

Prostanoids in scleroderma microangiopathy: clinical and pharmacoeconomic comparison between two intravenous regimens.

Objectives: Intravenous iloprost (ILO) has widely demonstrated its effectiveness and safety in systemic sclerosis (SSc) patients. Unfortunately, there is no clear consent about dosage, duration, frequency, and infusion modality. The aim of this study was to compare two different therapeutic schemes in the same cohort of consecutive SSc subjects, evaluating differences in terms of effectiveness [digital ulcer (DU) outcome], safety, and direct healthcare costs.Method: This was a retrospective observational study of 47 patients classified with SSc treated with intravenous ILO for severe Raynaud's phenomenon and/or DUs. Two regimens were compared: a continuous inpatient scheme and a daily outpatient scheme. Demographics and clinical data, concomitant therapies, adverse events, and data on resource use and costs were collected.Results: The number of DUs rose slightly with the switch from the continuous to the daily scheme (0.61 ± 1.2 vs 1.1 ± 1.7). Moreover, in the daily scheme there was an increase in the number of therapeutic cycles (2.4 ± 0.7 vs 4.71 ± 1.4, p < 0.001) and an increase in patients treated with other vasoactive drugs. There was a reduction in ILO tolerability and more than half of the patients suspended the treatment. Five patients required hospitalization for severe and refractory DUs in the daily scheme. Moreover, the costs of the two treatments were comparable [median 7174 (range 2748-18 524) EUR vs 6284 (3232-22 706) EUR, p = 0.712].Conclusion: Treatment with a daily scheme of ILO is characterized by worse tolerability and a higher dropout rate compared to a low-flow regimen, with similar costs. We suggest that a low-flow continuous therapeutic scheme is preferable in SSc patients.

Translation, cultural adaptation and validation of the Systemic Lupus Erythematosus Activity Questionnaire (SLAQ) in a cohort of Italian systemic lupus erythematosus patients.

Introduction The Systemic Lupus Erythematosus Activity Questionnaire (SLAQ) is a patient-reported instrument for the assessment of disease activity in systemic lupus erythematosus (SLE). The aims of the present study are translation, cultural adaptation and validation of an Italian version: the SLAQit. Methods The process of translation and cultural adaptation followed published guidelines. SLAQit was pretested in a group of 35 SLE patients to evaluate acceptability, comprehension and feasibility. Internal consistency, test-retest validity and external validity were tested on consecutive SLE patients attending the clinic. Results In total, 135 SLE patients were enrolled in this study. The pilot test provided a 99.9% response rate and demonstrated feasibility and comprehensibility of the questionnaire. A good internal consistency was found among the three components of the score (SLAQ score, numerical rating scale (NRS), patient global assessment question (PGA); α = 0.79). SLAQit showed very high reliability (test-retest α > 0.8). NRS and PGA showed a strong positive correlation with both Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) ( p = 0.002 and p < 0.001, respectively) and European Consensus Lupus Measurement (ECLAM) scores ( p = 0.01 and p < 0.001, respectively), while the SLAQ score did not. A significant agreement was observed between the physician's intention to treat and both the NRS and PGA scores, while no significant association was reported with the SLAQ score. Conclusions SLAQit was demonstrated to be a reliable and valid instrument for self-assessment of disease activity in SLE patients.

Post-occlusive reactive hyperaemia (POHR) in systemic sclerosis: very early disease (VEDOSS) represents a separate entity compared to established disease.

OBJECTIVES: Vascular involvement is a key feature of systemic sclerosis (SSc). Vascular changes are central to the pathogenesis of the disease and the assessment of vascular involvement has a prognostic value. This assessment therefore has a pivotal role in the management of SSc patients. The aim of our study was to evaluate post-occlusive reactive hyperaemia (PORH) in consecutive SSc patients and to test whether a PORH test might be a useful tool for the early diagnosis of SSc. METHOD: Between April 2011 and April 2015, 60 consecutive SSc patients (mean age 56 ± 15 years, females:males = 18:1) were enrolled in the study. The patients were divided into those with full-blown SSc (n = 50) and those with very early diagnosis of SSc (VEDOSS) (n = 10) according to the literature. Laser speckle contrast analysis (LASCA) was used to assess PORH. RESULTS: A statistically significant difference was detected in the post-ischaemic hyperaemic peak flow between VEDOSS and established SSc (424% vs. 137%, p = 0.0011). PORH peak flow decreased according to the capillaroscopic pattern (early = 419%, active = 163%, late = 145%, p = 0.0027). Moreover, a correlation between capillary density and peak flow was revealed (rho = 0.33, p < 0.01). CONCLUSIONS: These data show a different pattern of vascular involvement in VEDOSS compared to established disease that mirrors capillaroscopic changes. Functional features of very early and established disease seem to be the physiological counterpart of abnormalities detected by capillaroscopy. The POHR test might be a useful aid for further characterization of vascular involvement in SSc. In particular, blunted POHR might prove a tool to separate pre-clinical from full-blown SSc.

Systemic vasculitides: a critical digest of the most recent literature.

Herewith we provide our annual digest of the recent literature on systemic vasculitides. In this manuscript, we reviewed all the articles published during the last 12 months on large-, medium- and small-vessel vasculitis and selected the most relevant studies regarding the epidemiology, pathogenesis and management of systemic vasculitis. In particular, we focused the attention on giant cell arteritis, ANCA-associated vasculitis and cryoglobulinaemia.

Systemic sclerosis: a critical digest of the recent literature.

Systemic sclerosis is a complex disease characterised by chronic multisystem involvement of internal organs; every year many studies are published on the diagnosis, pathogenesis and treatment of the disease. In this article, we provide a critical analysis of the recent literature on systemic sclerosis, with particular focus on the most relevant studies published over the last two years.

Systemic vasculitis: a critical digest of the recent literature.

Herewith we provide a critical digest of the recent literature on systemic vasculitis. In this manuscript, we reviewed all the articles published during the last 12 months on large-, medium- and small-vessel vasculitis and selected the most relevant studies regarding the epidemiology, pathogenesis and management of systemic vasculitis. In particular we focused the attention on giant cell arteritis, ANCA-associated vasculitis and cryoglobulinemia.

Analysis of the prevalence of cataracts and glaucoma in systemic lupus erythematosus and evaluation of the rheumatologists' practice for the monitoring of glucocorticoid eye toxicity.

Chronic glucocorticoid (GC) therapy is associated with an increased risk of developing cataracts and glaucoma, and recommendations have been developed for monitoring these side effects in patients with rheumatic diseases. The aim of this study was to assess the prevalence of cataracts and glaucoma and the adherence to the existing recommendations for monitoring eye toxicity of chronic GC therapy among systemic lupus erythematosus (SLE) patients in routine clinical practice. Clinical charts of 170 patients were examined, and 34 (20%) of them never underwent an eye assessment. The remaining 136 underwent an eye assessment with an interval of 75 ± 61.7 months. Only 45 (33%) had received an evaluation during the previous 12 months. All these 170 patients were taking chronic CG therapy at a mean daily dose of 5.4 ± 2.4 mg prednisone and a mean cumulative dose of 27.6 ± 20.5 g. Out of the 136 patients with at least one eye assessment, cataracts were observed in 39 patients (29%) and glaucoma in 4 patients (3%). Cataracts were diagnosed at a mean age of 46.5 ± 10 years; the development of cataracts was associated with age, disease duration, and cumulative GC dose. Glaucoma was diagnosed at a mean age of 40.5 ± 16 years; due to the small number of patients, no correlations were made. The prevalence of cataracts and glaucoma is higher than in the general population, and these conditions occur early in the life of SLE patients. An association between GC and cataracts is confirmed. The adherence to recommendations is suboptimal as only 33% of patients underwent an eye assessment over the previous 12 months. These data reinforce the need to improve adherence to recommendations for eye monitoring among SLE patients under chronic therapy with GC.

Rhupus syndrome: assessment of its prevalence and its clinical and instrumental characteristics in a prospective cohort of 103 SLE patients.

The term "rhupus" is traditionally used to describe patients with coexistence of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). The aim of the present work was to investigate prevalence, clinical and radiological picture as well as the serological profile of a series of rhupus patients; SLE patients and RA patients from our Unit were used as disease control groups. A total of 103 consecutive SLE patients were screened; among the entire cohort, 10 patients (9.7%) were classified as "rhupus". In our rhupus patients SLE features preceded the onset of arthritis in 5 patients (50%) while in the remaining patients arthritis appeared before or simultaneously (3 and 2 patients respectively). As compared with SLE patients, rhupus patients have significantly less kidney involvement (p=0.01) while no differences were observed between neuropsychiatric, cutaneous, hematological involvement or serositis. At our physical examination, 9 (90%) rhupus patients were presenting active joint involvement; CRP positivity and ESR levels resulted significantly higher than in SLE (p=0.006) patients while no differences were observed with respect to RA patients. In all rhupus patients, at least one pathological finding was revealed by ultrasound (US) examination at wrist and/or hand joints; overall, rhupus patients presented higher scores in all the US parameters with respect to SLE patients, especially at hands; no statistically significant differences have been observed with respect to RA patients. Magnetic resonance (MR) revealed erosions in all rhupus patients with a concomitant bone edema in five patients. The cumulative erosive burden in rhupus patients was significantly higher than in SLE patients and similar to RA patients (SLE vs rhupus p=0.005); bone pathology distribution was also similar between rhupus patients and RA patients. These data suggest the importance of assessing joint involvement in SLE with advanced imaging techniques and of evaluating the presence of prognostic factors for joint disease severity in order to establish adequate disease monitoring and to institute early appropriate therapies to avoid late consequences of unrecognized concomitant rheumatoid arthritis (Amezcua-Guerra et al., 2006 [25]; Zhao et al., 2009 [26]).

Long-term cyclic intravenous iloprost in systemic sclerosis: clinical experience from a single center.

The aim of the present study was to retrospectively evaluate response to therapy in 73 patients affected by systemic sclerosis (SSc) who underwent long-term cyclic treatment with intravenous iloprost for peripheral vascular involvement (average duration of treatment 54.12±41.04 months). Seventy-three SSc patients were enrolled. Data were collected by reviewing clinical records and by phone or direct interview. Patients underwent a thorough physical examination at the end of follow up. The incidence of severe vascular manifestations was also assessed. Statistical analysis was performed by Wilcoxon's signed rank test and descriptive statistics using Statview software. In this study cohort, 55 of 73 (75.2%) patients had a history of ischemic digital ulcers (DUs); 28 patients (38.4%) had active DUs at the beginning of treatment. Skin ulcers healed completely in 25 of 28 patients (89.3%) at the end of the first treatment. However, 40 of 55 patients (72.6%) relapsed after an average of 24 months. There was a significant correlation between relapse rate and/or number of ulcers and clinical factors (diffuse subset, changes in results of Allen's test, NT-pro BNP levels). The annual incidence of pulmonary arterial hypertension (PAH) was 2.34 (95%CI: 0.94-4.83) per 100 person years, the rate of gangrene was 2.7%, and no cases of scleroderma renal crisis were recorded. The incidence of PAH and of digital gangrene was higher than that observed in unselected SSc case series. These data suggest that our patients treated with iloprost have a higher vascular involvement than large case series of unselected SSc patients. A number of clinical factors are correlated to the severity of vascular involvement and could have an impact on the response to therapy. The clinical significance of these findings requires clarification and further investigation is needed.

How HCV has changed the approach to mixed cryoglobulinemia.

Mixed cryoglobulinemia is a systemic disease due to a small vessel immune-complex mediated vasculitis. The discovery of a viral origin of the disease has launched a great expectancy among researchers and the years after this finding have been characterized by the effort to reach viral eradication in the hope of obtaining disease remission. Moreover, the use of immunosuppressives has been discouraged for many years as they could favour viral replication, and HCV infection has represented a contraindication to the more recent biological drugs directed against cytokines. The trials with antiviral agents in this disorder, however, has not met the expectations, especially when challenged with some of the most severe complications of the disease; moreover, these medications were not devoid of unexpected side effects, such as the occurrence of peripheral neuropathies. Since lymphoproliferation is one of the features of the disease, this has focused the attention of investigators on the potential benefit of newly targeted therapies specifically directed against B-lymphocytes (such as rituximab). Preliminary results on the use of these medications are promising. Furthermore, the use of biological agents in small open trials in HCV positive arthritis patients has demonstrated an acceptable safety profile. All these empirical observations should probably induce the scientific community to reconsider the therapeutical approach to HCV-related mixed cryoglobulinemia. Indeed, the use of aggressive chemotherapy treatments in the era preceding HCV discovery has not been associated with significant liver toxicities and standard chemotherapy during HCV-related lymphoma carried out a unexpected low rate of severe liver damage. Future efforts should probably focus on the potential benefit of a multi-step, combined anti-viral and cytotoxic therapy (both with standard regimens and new medications).

[Churg-Strauss syndrome: outcome and long-term follow-up of 38 patients from a single Italian centre]. / Caratteristiche clinico-sierologiche e dati di out come di una casistica monocentrica di pazienti affetti da sindrome di Churg-Strauss.

OBJECTIVE: This study was aimed at verifying any potential correlation between anti-myeloperoxidase antineutrophil cytoplasmic antibodies (ANCA-MPO) and clinical features and outcome indices in Churg-Strauss Syndrome (CSS). METHODS: Thirty-eight Churg-Strauss syndrome patients were selected from the medical records of all vasculitis patients attending the Rheumatology and Immunology Unit at the Department of Internal Medicine of the University of Pisa in the decades between 1989 and 2008. Data were analysed retrospectively. Statistical analyses of the results were carried out using the Mann-Whitney test to determine the correlations between the clinical and serological parameters. Qualitative variables were compared using contingency table analysis and Fisher's exact test. RESULTS: ANCA-MPO were detected in15/38 (39%) patients. Positive ANCA status was associated with peripheral neuropathy (p=0.0006), whereas negative ANCA status was associated with lung involvement (p=0.002). Relapses were strongly associated with positive ANCA status (p=0.01) and with an increase in- or a reappearance of ANCA-MPO levels (p=0.006). Finally, ANCA-MPO were significantly associated with neurological damage (p=0.003). CONCLUSIONS: The presence or absence of ANCA-MPO identify different clinical subsets in CSS. Overall, ANCA-MPO appears as a useful tool in the monitoring of CSS and in particular a good predictor of CSS relapses.

Mixed cryoglobulinemia and mortality: a review of the literature.

Mixed cryoglobulinemia is a highly heterogeneous clinical syndrome in terms of clinical presentation, extent and severity of organ involvement, immunological abnormalities and clinical course. Modern management began with the discovery of the close association between this syndrome and hepatitis C virus (HCV) infection. In this review we examined previously published studies on mortality in different series of patients with mixed cryoglobulinemia (MC). Patients with mixed cryo-globulinemia have higher mortality rates, predicted by age, renal involvement, intestinal vasculitis, widespread vasculitis and type of cryoglobulins.

[Ultrasound lung comets: new echographic sign of lung interstitial fibrosis in systemic sclerosis]. / Le comete ultrasoniche polmonari (ULC): un nuovo segno ecografico di fibrosi polmonare nella sclerodermia.

OBJECTIVE: Interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH) are common complications of systemic sclerosis (SSc). Echocardiography evaluates PAH, and chest sonography detects even mild ILC as ultrasound lung comets (ULC), i.e. multiple comet-tails fanning out from the lung surface and originating from subpleural interlobular septa thickened by fibrosis. AIM: to assess ILaD and PAH by integrated cardiac and chest ultrasound in SSc. METHODS: We enrolled 30 consecutive SSc patients (age= 54+/-13 years, 23 females) in the Rheumatology Clinic of Pisa University. In all, we assessed systolic pulmonary arterial pressure (SPAP), from maximal velocity of tricuspid regurgitation flow, and ULC score with chest sonography (summing the number of ULC from each scanning space of anterior and posterior right and left chest, from second to fifth intercostal space). All patients underwent plasma assay for anti-topoisomerase antibodies (anti-Scl70), and antiicentromere associated with development of pulmonary involvement. Twenty-eight patients also underwent high resolution computed tomography, HRCT (from 0= no fibrosis to 3= honey combing). RESULTS: ULC number - but not SPAP - was correlated to HRCT fibrosis and presence Scl-70 antibodies. ULC number was similar in localized or diffuse forms (16+/-20 vs 21+/-19, p=ns) and was unrelated to SPAP (r=0.216, p=ns). CONCLUSIONS: Chest sonography assessment and ULC allow a complete, simple, radiation-free characterization of interstitial lung involvement in SSc - all in one setting and with the same instrument, same transducer and the same sonographer. In particular, ULC number is associated with HRCT evidence of lung fibrosis and presence of Scl-70 antibodies.

[Churg-Strauss vasculitis and idiopathic hypereosinophyl syndrome: role of molecular biology in the differential diagnosis of hypereosinophyl syndrome]. / Vasculite di Churg-Strauss e sindrome ipereosinofila idiopatica: ruolo della biologia molecolare nella diagnosi differenziale delle sindromi ipereosinofile.

OBJECTIVE: Hypereosinophilic syndromes are a heterogeneous group of uncommon disorders characterized by the presence of marked peripheral blood eosinophilia, tissue eosinophilia, or both, resulting in a wide variety of clinical manifestations, often without an identifiable cause. Churg-Strauss syndrome is a systemic vasculitis characterized by prominent peripheral eosinophilia, asthma and systemic involvement. The presence of mild to severe eosinophilia and systemic involvement raise the search of many trigger factor that need to be ruled out. Distinguishing CSS from idiopathic hypereosinophilic syndrome may be particularly challenging, especially in ANCA negative patients. METHODS: The aim of the present study was to present a small case series of patients referred to a Rheumatology Unit for mild to severe eosinophilia and signs and symptoms of systemic involvement and to outline the clinical significance of molecular biology in the work-up of hypereosinophilia. RESULTS: Eleven patients with moderate to severe peripheral eosinophylia, were referred to our Unit from 1996 to 2007. Female to male ratio was 7/4, mean age 40.54 (range 22-75). Three out of eleven patients resulted positive for molecular biology. The diagnosis of idiopathic hypereosinophylia was confirmed in one out of three on the basis of the clinical picture and bone marrow biopsy. CONCLUSIONS: Molecular biology may be useful in the screening and in the follow-up of a new hypereosinophylic patient.

[Analysis of the evolution to defined connective tissue diseases of patients with "early unidifferentiated connective tissue diseases (UCTD)"]. / Evoluzione verso connettiviti definite in una popolazione di pazienti affetti da "early undifferentiated connective tissue disease"

The term undifferentiated connective tissue diseases (UCTD) is used to identify systemic autoimmune diseases not fulfilling classificative criteria for defined connective tissue diseases (CTD). Aim of the present study was to evaluate the evolution to defined CTD of an historical cohort of 91 UCTD patients followed at our Unit and to describe clinical and serological characteristics of stable UCTD patients with a disease duration of more than 5 years. Patients, previously described, were selected for having an undifferentiated profile after 1 year of follow up. These patients have been regularly followed at our Unit and their diagnosis has been reassessed annually based on the existing classificative criteria. Seven UCTD patients with a follow up of less than 5 years have been excluded from the study, therefore 84 patients (F: 81, M: 3) have been analysed. During the follow up 28 patients (33%) developed a defined CTD. In particular 22 patients developed systemic lupus erythematosus (SLE), while the remaining 6 patients developed other CTDs (2 primary Sjögren's syndrome, 2 overlap syndromes, 1 Systemic Sclerosis, 1 rheumatoid arthritis). The evolution to a defined CTD occurred after a mean disease duration of 80.6+/- 66.8 months (min 14, max 336, median 72); the evolution to SLE occurred after a mean disease duration of 66.8+/-43.3 months (min 17, max 216, median 57). Anti-cardiolipin antibodies were the only variable correlated with the evolution to SLE (p<0.05). Stable UCTD were characterized by a simplified clinical picture with no major organ involvement and by a simplified autoantibody profile (anti-Ro/SSA antibodies and anti-RNP antibodies were the single antibody specificities observed in 22% and 13% of patients respectively). These results confirm previous data showing that about 30% of UCTD patients will develop a defined CTD, the predictive role of anti-cardiolipin antibodies for the evolution to SLE, and the existence of stable UCTD, distinct clinical entities with a simplified clinico-serological profile. The early identification of stable UCTD is very important both from a clinical and a research point of view. Future research is needed to define a new set of classification criteria.

Blunted increase of digital skin vasomotion following acetylcholine and sodium nitroprusside iontophoresis in systemic sclerosis patients.

OBJECTIVES: To test the hypothesis that finger skin vasomotion (FSV), a known factor influencing microvascular blood flow motion, is impaired in SSc patients. Possible relationships between FSV abnormalities and the severity and/or activity of SSc were also investigated. METHODS: FSV was investigated by means of spectral Fourier analysis of finger skin laser Doppler flowmetry (LDF) tracing, recorded before and following acetylcholine (ACh) or sodium nitroprusside (SNP) iontophoresis in 26 SSc patients and in 20 age-matched healthy controls. The power spectral density (PSD) of the 0.01-0.02, 0.02-0.06 and 0.06-0.2 Hz LDF oscillations (related to endothelial-, sympathetic- and myogenic-dependent FSV, respectively) was measured in PU(2) (perfusion units)/Hz. RESULTS: Compared with controls, SSc patients exhibited a significantly lower post-ACh and/or post-SNP percentage increase in PSD of 0.01-0.02 Hz (492 +/- 297% vs 283 +/- 167%; P < 0.005), of 0.02-0.06 Hz (336 +/- 205% vs 239 +/- 170%; P < 0.05) and of 0.06-0.2 Hz (223 +/- 91% vs 194 +/- 227%; P < 0.01) skin LDF oscillations. The post-SNP normalized PSD value of the 0.01-0.02 Hz and of the 0.02-0.06 Hz LDF oscillations was negatively related to SSc severity index (r = -0.407, P < 0.05 and r = -459, P < 0.05, respectively). CONCLUSIONS: This study showed a selective abnormality of the endothelial, sympathetic and myogenic-dependent FSV in SSc patients, consistent with a parallel endothelial, sympathetic and myogenic macrovascular dysfunction. This study also suggests a possible role of endothelial and sympathetic dysfunction in the progression of SSc.